Alendronate for the treatment of osteoporosis in men

WP Olszynski† & KS Davison
†Rheumatology Associates, Canadian Multicentre Osteoporosis Study, #103, 39-23rd St. East, Saskatoon, SK, S7K 0H6, Canada

Background: Men have higher rates of osteoporosis and suffer fragility fractures more often than previously believed. Fracture-related morbidity and mortality in men is substantially higher than in women. Objective: To investigate alendronate for treating osteoporosis in men. Methods: Search limited to ‘men’ and ‘English’; keywords were ‘osteoporosis’ or ‘bone density’ or ‘fracture’ and ‘alendronate’. Results/conclusions: Alendronate is an amino-bisphosphonate with proved efficacy for increasing bone mineral density in men with idiopathic or secondary osteoporosis and has demonstrated an ability to prevent vertebral fractures in men with low bone mass. There are trends for alendronate to decrease the risk of non-vertebral fracture, but larger trials are needed to conclusively establish this benefit. Alendronate is a well-tolerated and comparatively safe drug with an attractive once-a-week dosing regimen.

Keywords: alendronate, bone mineral density, fracture, generic, idiopathic, men, osteoporosis, primary, secondary

Expert Opin. Pharmacother. (2008) 9(3):491-498

1.Introduction

Osteoporosis and fragility fractures are increasingly a reality for men as they age. By World Health Organization criteria, nearly 20% of men > 50 years old have osteoporosis [1] and ∼ 13% of US white men and up to 22% of European men
> 50 years old are predicted to suffer a fragility fracture in their remaining lifetime [2,3]. Men experience 25 – 30% of all hip fractures [4-6] and approxi- mately half of all vertebral deformities [7-12]. Furthermore, morbidity and hip fracture-related mortality are substantially higher in men as compared with women [13,14].
The pathophysiology of osteoporosis in men is often multifactorial, thus complicating its study. Lower rates of fracture in men compared with women are theorized to be a consequence of men’s larger bone structure, reduced archi- tectural disruption, greater bone accrual during growth, earlier mortality, fewer falls and lower bone turnover rates [15]. With the exception of the menopause in women, after 30 years of age the rate of bone loss is similar between men and women [16-19]. However, in osteoporotic women trabecular number is reduced, whereas in osteoporotic men trabecular thickness is reduced [20]. This subtle difference in where bone is lost may account for some of the differences in fracture prevalence between men and women.
Secondary causes of bone loss in men are common, with the most frequent being alcohol abuse, glucocorticoid excess (endogenous or exogenous) and hypogonadism [21]. In men, low estrogen levels have been shown in some studies to be the most significant determinant of increased bone turnover and accelerated bone loss in both idiopathic and hypogonadal osteoporosis [22]. There may be

10.1517/14656566.9.3.491 © 2008 Informa UK Ltd ISSN 1465-6566 491

enough similarity in the development of osteoporosis between men and women that antifracture therapies proven for women may also be beneficial for men.

2.Overview of the market

Etidronate disodium was the first bisphosphonate for the treatment of postmenopausal osteoporosis and is still available in many markets today. Alendronate was the first amino-bisphosphonate to reach market for the treatment of postmenopausal osteoporosis and has since been joined by risedronate, ibandronate, pamidronate and zolendronate, although not all are approved for the treatment of osteoporosis in all countries. The amino-bisphosphonates have comparable mechanisms of action, resulting in dramatic decreases in bone resorption and fracture risk.
Teriparatide, a synthetic analog of parathyroid hormone, recently entered the market as an anabolic therapy that possesses the ability to increase bone mass and decrease fracture risk in postmenopausal women. In some markets strontium ranelate has been introduced possessing both anabolic and antiresorptive properties; it, too, has been shown to positively impact fracture risk in postmenopausal women. Lastly, denosumab, a biologic therapy shown to decrease bone resorption through its interference with RANK-ligand, is under review through ongoing Phase III trials.
There are data on the efficacy of osteoporosis treatment with both risedronate and teriparatide in men, both with favorable effects [23-27]. However, alendronate stands alone in the treatment of men with osteoporosis – it possesses more data regarding this indication than the others combined.

3.Alendronate

Alendronate has been proved to increase bone mineral density (BMD) and reduce fracture risk at vertebral and non-vertebral sites in postmenopausal women [28-31] and its safety and efficacy has been demonstrated for up to 10 years [32]. However, the safety of long-term administration of alendronate has recently come under some scrutiny – it has been suggested that the dramatic suppression of bone turnover that is characteristic of alendronate therapy may, over many years, decrease the skeleton’s ability to remodel those areas that have suffered mechanical damage. Over time this microdamage may coalesce and may increase an individual’s risk of fragility fracture. Odvina et al. [33]
and a study recently reported in abstract form by Lenart et al. [34] have both reported atypical low-energy fractures in women who were on long-term alendronate therapy. A recent meta-analysis confirmed that alendronate was efficacious in preventing fragility fractures and increasing BMD in women with prior fractures or with low BMD [35]. Although the antifracture efficacy of alendronate is well established for postmenopausal women, it is less well-studied in men.

4.Chemistry, pharmacodynamics, pharmacokinetics and metabolism

Alendronate is an oral medication that has an extremely low gastrointestinal absorption – ∼ 0.7% is absorbed into circu- lation with no gender differences. It is administered in a fasted state with water; if it is taken with food or drinks other than water it is quickly bound and becomes inert. Once in circu- lation, 40 – 60% is rapidly bound to bone, with virtually no retention in other tissues. Unbound alendronate is rapidly eliminated via renal excretion. Bound alendronate becomes incorporated into the bone and is only released once a new remodeling occurs within the same location, which can take a period of years. Once the alendronate is freed from the bone it can again bind to a new skeletal site and display the same antiresorptive properties [36].
The primary action of alendronate is to decrease osteoclastic activity by way of interfering with the melonovate pathway and protein prenylation within the osteoclast [37,38]. The result of these actions is decreased osteoclast-mediated bone resorption and a preservation of bone.

5.Clinical efficacy

5.1Alendronate for the management of idiopathic osteoporosis in men
The majority of trials investigating the efficacy of alendronate in men have included men with secondary osteoporosis, but a number of investigations have reported on the effects of alendronate on treating idiopathic osteoporosis.
One of the most compelling trials supporting the use of alendronate in men with low BMD was by Orwoll et al. [39]. This investigation was the largest trial investigating the impact of alendronate on BMD and vertebral fracture risk in men. In this 2-year double-blind, placebo-controlled randomized controlled trial (RCT) of 241 osteoporotic men, approximately a third of the men had low serum-free testosterone concentrations at baseline. All participants received calcium and vitamin D supplements. After 2 years of alendronate therapy (10 mg/day) the mean increase in BMD was significantly higher (p < 0.001) at all measured sites in the alendronate group as compared with the placebo group: at the lumbar spine (LS) there was a mean 7.1% increase in BMD in the alendronate group and a 1.8% increase in the placebo group; at the femoral neck (FN) a mean 2.5% increase in BMD for the alendronate group compared no change in the placebo group. There was a significantly (p = 0.02) lower quantitatively assessed morphometric vertebral fracture incidence in the alendronate group compared with the placebo group (0.8 versus 7.1%).
Ringe et al. [40] reported that 2 years of therapy with alendronate 10 mg/day was superior to 2 years of therapy with alfacalcidiol 1 µg/day for increasing BMD in 134 men with idiopathic osteoporosis. In this open-labeled RCT, all men also were administered 500 mg/day of supplemental

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calcium; no other vitamin D was provided. Following 2 years of therapy, the active-control group had increases of 2.8 and 2.2% BMD at the LS and FN, respectively, whereas the alendronate group’s changes were 10.1 and 5.2%, respectively. There was a trend (p = 0.071) for the alendronate group to have lower rates of new morphometrically assessed vertebral fracture (7.4%) as compared with the alfacalcidiol group (18.2%). Ringe et al. [41] extended their open-label trial to 3 years and after the additional year of follow up and therapy the increases in BMD for both groups were largely the same as in year 2; however, new vertebral fractures occurred in 24.2% of the alfacalcidiol-treated patients and in 10.3% of the alendronate-treated patients (p = 0.04), thus demonstrating a significant vertebral anti- fracture benefit of alendronate after 3 years of therapy as compared with an active-control. It must be noted that in this trial there was a small sample size and a small number of frac- ture events; in light of this, the fracture outcomes reported here need to be supported with larger, prospective trials.
Ho et al. [42] investigated the role of one year of alendronate 10 mg/day treatment in the management of osteoporosis in men and women with either primary or secondary osteoporosis with at least one vertebral fracture. The primary outcome measure in this prospective, controlled, open-label study was change in LS BMD over the year of therapy. The study was split into a number of cohorts, most relevantly to men with primary (n = 23) or secondary osteoporosis (n = 18), and male (n = 29) untreated controls. Calcium was administered to the control patients (500 mg/day) and no vitamin D use was reported for any group. There was no significant BMD change in the control group at any site at any time. For the men with primary osteoporosis there was a mean 7.0% increase in LS BMD (p < 0.001) and a 2.6% increase in trochanteric BMD (p = 0.08) after 12 months of therapy when compared with baseline. For the men with secondary osteoporosis, there was a mean 6.4% increase in LS BMD (p = 0.06) and a 3.7% increase in trochanteric BMD (p < 0.05) after 12 months of therapy compared with baseline. No significant changes in BMD were observed at the FN for any group.
Gonnelli et al. [43] investigated the efficacy of alendronate 10 mg/day with calcium 1 g/day compared with calcium 1 g/day alone in a cohort of 77 men with idiopathic osteoporosis over a span of 3 years. Vitamin D was not provided to either group. BMD at the LS, FN and total hip (TH) were measured at baseline and after each year of therapy. Significant (p < 0.05) BMD gains were realized after the initial year of alendronate therapy: LS 4.2%, FN 2.1% and TH 1.6%. After 3 years the gains continued: LS 8.8%, FN 4.2% and TH 3.9% (p < 0.05). The calcium- only group remained largely unchanged, or slightly decreased, from baseline. The changes in BMD from baseline with alendronate therapy were similar in magnitude to the other studies of idiopathic osteoporosis in men.

Olszynski et al. [44] examined data from the Canadian Database of Osteoporosis and Osteopoenia patients to determine if there was a difference in changes in BMD among osteoporotic men administered etidronate, alendronate or no bone-active therapy over a 1-year period. A total of 244 men were included in the study (42 alendronate, 102 etidronate and 100 control). Differences in the per cent change in BMD from baseline were most notable at the LS in favor of alendronate (4.3%) and etidronate (2.1%) therapy when compared with controls. There were no significant differences in percent change in FN BMD among any of the groups, although they trended in the same way as LS BMD. Alendronate therapy resulted in significant (p < 0.05) gains in LS BMD as compared with etidronate therapy, and both bisphosphonates were significantly (p < 0.05) better than the men who were not administered a bisphosphonate.
Sawka et al. [45] performed a meta-analysis on the effect of alendronate in men. After systematically searching for all applicable articles (103 found) and excluding those that did not meet the inclusion criteria for the proposed analysis, the authors were left with two studies to combine for an esti- mate of vertebral and non-vertebral fracture efficacy. Studies of men with secondary causes of osteoporosis other than hypogonadism were excluded. The odds ratios of incident fractures in men (with 95% credibility intervals) with alendronate 10 mg/day were: vertebral fractures, 0.44 (0.23, 0.83) and non-vertebral fractures, 0.60 (0.29, 1.44). The findings were similar to those found in the meta-analysis of the effect of alendronate in postmenopausal women by Cranney et al. [35].
Finkelstein et al. [25] tested the effects of alendronate (10 mg/day; 28 men), parathyroid hormone (40 µg s.c. daily; 27 men) and the two combined (28 men) on BMD in an attempt to uncover a possible synergistic or additive effect of the two therapies over a 30-month period (parathyroid hormone therapy begun at month 6). LS and FN BMD increased significantly more in men treated with parathyroid hormone alone than men treated with alendronate or the combination. LS BMD also increased significantly more in the combination-therapy group than in the alendronate-only group. The authors concluded that alendronate impairs the ability of parathyroid hormone to increase LS and FN BMD in men, which was theorized to be attributable to an attenuation of parathyroid hormone-induced stimulation of bone formation by alendronate.

5.2Alendronate for the management of glucocorticoid-induced osteoporosis and other secondary causes
Glucocorticoid use is a major cause of secondary osteoporosis in men and women. Osteoporosis and associated fractures are the most common complication of glucocorticoid use and result in significant pain, disability and morbidity [46]. Glucocorticoid therapy rapidly increases the risk of fracture,

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within 3 – 6 months of administration, and results in fracture in many of those who are administered them [47,48]; therefore, any prophylactic therapy that could preserve bone mass during glucocorticoid therapy is a welcome asset. In an extensive chart review of long-term glucocorticoid users (> 3 months) BMD testing was ordered for less than half of the glucocorticoid-treated patients and less than a third were taking prophylactic bisphosphonate therapy [49].
Amin et al. [50] performed a meta-analysis of 45 trials to determine the efficacy of a number of therapies in the management of glucocorticoid-induced osteoporosis as assessed by the change in LS BMD. They included all trials that were longer than 6 months in duration, had an RCT design, and were administered oral glucocorticoids. The results demonstrated that gains in LS BMD were larger with bisphosphonate therapy than with calcium, vitamin D or calcitonin therapy and that the efficacy of bisphosphonates was significantly enhanced when they were administered along with vitamin D.
Adachi et al. [51] investigated the efficacy of 2 years of alendronate therapy (2.5, 5 or 10 mg/day) in a cohort of long-term glucocorticoid users (> 7.5 mg/day prednisone or equivalent). The investigation was a double-blind, placebo-control trial and all patients received calcium 800 – 1000 mg/day and vitamin D 250 – 500 IU for the duration of therapy. Treatment with alendronate led to significant gains in BMD at all assessed sites in both men and women, with the men displaying slightly larger gains as compared with the women in the active arm. This data demonstrated not only that alendronate was efficacious in the treatment of glucocorticoid-induced osteoporosis in men, but that it also appears to have a greater effect than in women; the increases in LS BMD were ∼ 2% higher in men as compared with women after 24 months.
Androgen deprivation therapy (ADT) in men with prostate cancer is associated with bone loss and fractures. Greenspan et al. [52] sought to determine whether once- weekly oral alendronate (70 mg once-a-week) could prevent bone loss and reduce bone turnover in 112 men receiving ADT. The trial was a double-blind, placebo-controlled RCT. All patients received either alendronate or placebo once weekly in addition to calcium and vitamin D supplementation. After 1 year, men treated with alendronate had significant gains in BMD of 3.7% at the LS and 1.6% at the FN, whereas men in the placebo group had losses of 1.4% at the LS and 0.7% at the FN. Bone turnover significantly decreased with active therapy compared with placebo.
The use of alendronate to minimize the bone loss associated with antirejection therapies after renal transplantation has been investigated by a number of studies. Frequent use of glucocorticoids, use of ciclosporin and ciclosporin-like agents and persistent hyperparathyroidism used in transplantations create a state of accelerated bone turnover and increased fracture risk. Over a 1-year period, El-Agroudy et al. [53]
followed 60 adult male recent renal transplant recipients

who were divided into one of four groups: daily alphacalcidol 0.5 mg/day orally; oral alendronate 5 mg/day; intranasal salmon calcitonin 200 IU every other day; and a control group (all groups supplemented with calcium 500 mg/day). LS BMD increased by 0.8% and FN BMD by 0.6% with alendronate therapy, whereas it decreased by 3.2 and 3.8%, respectively, in the control group. This study demonstrated that early bone loss that occurs during the first 12 months after renal transplantation could be prevented by alendronate. An investigation by Gianni et al. [54] investigated the effects of alendronate on bone loss after renal transplantation and similarly found that alendronate was successful in preserving bone in an environment of rapid bone loss, even years after the renal transplantation. Another investigation reported that alendronate was slightly more effective in restoring BMD than calcitriol treatment in long-term renal transplant recipients [55]. Considering the higher rate of fractures, antiresorptive therapy can be an alternative to vitamin D analogs not only to prevent further loss, but also to restore BMD in long-term renal transplant recipients.
There are a number of other conditions where alendronate has been shown to preserve or increase bone mass in situations where there are high levels of bone turnover and increased fracture risk: alendronate has been demonstrated to reduce bone loss and preserve bone mass in sarcoid patients [56], and in reducing bone loss and maintaining bone in HIV/AIDS patients undergoing highly active antiretroviral therapy [57,58].
Even hypogonadal men who are receiving standard testosterone replacement have been shown to benefit from alendronate in the preservation of bone mass over a 36-month period. Significant increases in LS and FN BMD have been observed after 1, 2 and 3 years of therapy with alendronate when combined with testosterone replacement [59].

6.Safety and tolerability

Alendronate, particularly in its weekly dosing schedule (70 mg once-a-week), has been shown to be a very safe and tolerable drug with an exceedingly low adverse-event profile. No substantial drug interactions have been identified. There have been reports of upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis or ulcer from use of alendronate [60-63]. The incidence of these gastrointestinal side effects has been demonstrated in large RCTs to be no more common with the alendronate-treated groups than observed within the placebo groups [64-67]. Contraindications to the use of alendronate include abnormalities of the esophagus, which delay esophageal emptying such as stricture or achalasia, inability to stand or sit upright for at least 30 min, and those with hypocalcemia.

7.Conclusion

Although the underlying pathophysiology of osteoporosis may differ between men and women, the similar response of

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BMD in men to alendronate suggests that the skeletal response to bisphosphonates is not gender specific. When examining the data regarding the treatment of men and women with alendronate it should be noted that the cohorts of men used in clinical trials have been ∼ 10 years older than the comparable trials in women and that, on average, the men possessed more co-morbidities than their female counterparts. Both of these differences may be expected to result in a greater response to therapy in the men’s cohorts than in the women’s.
As is typical of the bisphosphonates in the treatment of postmenopausal women, there were rapid increases in BMD during the initial year of alendronate therapy in men with both idiopathic and secondary osteoporosis, consistent with the filling of numerous resorption lacunae with bone mineral. Gradual gains through 3 years of alendronate therapy were also observed in men with typical gains in BMD of 5 – 10% at the LS and 3 – 5% at the proximal femur.
The use of alendronate for the treatment of idiopathic osteoporosis in men is well supported: there is clear evidence for a beneficial effect of alendronate on LS and proximal femur for up to 3 years and evidence to support its use for the prevention of fragility fractures in men with low bone mass and/or prevalent vertebral fractures. The use of alendronate to minimize the losses of bone with secondary causes of osteoporosis such as glucocorticoids is also well supported.
There is little data supporting the antifracture efficacy of alendronate in men. Due to small sample sizes and to low fracture rates very few investigations have had the power to identify such a benefit. Although the efficacy of alendronate in preventing vertebral fractures in men with idiopathic osteoporosis has been determined, the effect of alendronate on non-vertebral fracture has not been conclusively established, although the trends suggest that there most likely is an effect. To our knowledge, there is no men-only trial that has proved antifracture efficacy in men treated with alendronate for secondary osteoporosis. Larger antifracture trials in men with low bone mass are needed.

8.Expert opinion

There is no bisphosphonate available today with more clinical data regarding its use for the treatment of osteoporosis is men than alendronate. However, there is accumulating evidence for the efficacy of both risedronate and teriparatide in the treatment of osteoporosis in men [23,24,26,27]. Further supporting the use of alendronate is the data from post- menopausal women that demonstrates both the efficacy and safety of alendronate over ten years of therapy [32]. However, the long-term safety of alendronate administration is not without controversy, particularly over concerns with over- suppression of bone turnover leading to greater risk of atypical low-energy fractures [33,34].
From the available evidence, it appears that the effect of alendronate on BMD is similar in men and women – in

fact, the majority of comparative studies demonstrate a greater BMD response to alendronate in men than in women. Although only a few trials have had the power to study the efficacy of alendronate for decreasing fracture risk, particularly non-vertebral, the data are encouraging and suggest that with larger trials the efficacy of alendronate for decreasing fracture risk would be further strengthened.
The more infrequent dosing schedule (70 mg once-a-week versus 10 mg/day) should translate into better adherence to therapy and, therefore, better outcomes. Alendronate has demonstrated to be a well-tolerated therapy with very few side effects.
Alendronate has recently begun including colecalciferol 5600 IU with its weekly (70 mg once-a-week) dose of alendronate in an attempt to optimize vitamin D status of the individual as a number of investigations and at least one meta-analysis has suggested that the efficacy of bisphosphonates is augmented with concomitantly administered vitamin D. The addition of vitamin D to the formulation is beneficial for patients, particularly those who may not receive adequate vitamin D from their diet or from exposure to sunlight.
The market has recently become awash with valid options for osteoporosis treatment when only a decade ago there were few real choices. The introduction of new amino-bisphosphonates with weekly, bimonthly, monthly and even yearly administration will certainly vie for market share from alendronate. Teriparatide, although a promising therapy for the treatment of osteoporosis, has been reserved for only the worst cases of osteoporosis and partnered with the cost and the route of administration is unlikely to command much market share from alendronate. The impact of strontium ranelate and denosumab has yet to be determined.
There is evidence that a course of teriparatide (18 months) to build up bone as much as possible, followed by administration of alendronate to preserve bone at the new, higher bone mass, may be possible. More studies investigating the use of teriparatide followed by alendronate need to be completed. Certainly, the two therapies should not be administered at the same time as alendronate has been demonstrated to blunt the actions of teriparatide when they are administered concomitantly. Recent data presented in abstract form at the American Society for Bone and Mineral Research Annual Meeting [68] suggested that women previously treated with alendronate or raloxifene had a positive response to administration of teriparatide either as a replacement for their antiresorptive therapy or as an adjunct to it. Adding the teriparatide caused smaller increases in bone turnover as com- pared to switching to teriparatide and adding teriparatide caused greater increased in BMD as compared with switching to teriparatide. These differences were more marked within the alendronate groups as compared to the raloxifene groups.
Generic versions of alendronate are available in almost all markets that the original formulation is available in. This occurrence has had a dramatic impact on the market share of the original formulation and most likely spells the end of

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large trials with alendronate. Although generic alendronate is similar to the original, there has been documented evidence of vastly different dissolution profiles between the generics, with some dissolving extremely rapidly and others extremely slowly [69]. Those that dissolve very rapidly may have an increased negative impact on the esophagus and those that dissolve very slowly may pass through the body without being absorbed, particularly considering the extremely low solubility of alendronate to begin with. It is the opinion of the authors that the efficacy demonstrated with the original formulation should not necessarily be extended to the generic versions of alendronate; it should be required that generic versions prove efficacy in antifracture trials similar to those which were required for the original formulation.

In the next 5 – 10 years, the market share of the original formulation of alendronate will most likely be dramatically eroded by the arrival of the generics. Until that time valuable effectiveness data on the original alendronate will accumulate to further support the use of alendronate for the treatment of osteoporosis in men.

Declaration of interest

WP Olszynski is consultant for Merck Frosst Canada and Wyeth Canada.
KS Davison is a consultant for Servier Canada and is a consultant for and has received speakers’ fees from Merck Frosst Canada, Procter & Gamble Canada and sanofi-aventis Canada.

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Affiliation
WP Olszynski†1 MD PhD & KS Davison2 PhD †Author for correspondence
1Clinical Professor of Medicine University of Saskatchewan, Saskatoon, SK, Canada Director
Saskatoon Osteoporosis Centre, Saskatoon, SK, Canada
Director
Rheumatology Associates,
Canadian Multicentre Osteoporosis Study, #103, 39-23rd St. East, Saskatoon,
SK, S7K 0H6, Canada
Tel: +1 306 244 2277; Fax: +1 306 244 6755; E-mail: [email protected]
2Clinical Scientist Laval University, Quebec, PQ, Canada Clinical Scientist
Saskatoon Osteoporosis Centre, Saskatoon, SK, Canada
Co-Director
Canadian Multicentre Osteoporosis Study, #103, 39-23rd St. East, Saskatoon,
SK, S7K 0H6, Canada

498 Expert Opin. Pharmacother. (2008) 9(3)